Asenapine or trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole, was first described in U.S. Pat. No. 4,145,434 by van der Burg and is represented by a structure of Formula 1:

Asenapine is a broad-spectrum, high potency serotonin, noradrenaline and dopamine antagonist, which exhibits potential antipsychotic activity. Asenapine is marketed as its maleate salt for the treatment of schizophrenia and manic episodes associated with bipolar I disorders, in the form of sublingual tablets sold under the trademark SAPHRIS®.
Pharmaceutical compositions comprising asenapine maleate for sublingual or buccal administration were first described in EP 0 746 317 B1. These sublingual tablets were prepared by a freeze-drying (lyophilisation) process. This process involves freezing off an aqueous-based drug solution followed by sublimation of the ice in a vacuum, an undesirable process for industrial scale applications.
As described in Funke et al., Arzneim.-Forsch./Drug Res., 40:536-539 (1990), asenapine maleate (Form H) was the first known polymorphic form. Form H is a monoclinic crystalline form having a melting point in the range of 141° C. to 145° C. EP 1 710 245 B1 and EP 1 917 267 B1 described the discovery of a new form of asenapine maleate (Form L), which is an orthorhombic crystalline form having a melting point in the range of 138° C. to 142° C. EP 1 710 245 B1 and EP 1 917 267 B1 mention the importance of the particle size of asenapine maleate, since asenapine maleate is commercialised as sublingual tablets, which are dissolved in the mouth. Thus, asenapine maleate having a particle size distribution characterised by a d95 of about 100 μm or less, more preferably about 50 μm or less, and most preferably about 30 μm or less is desirable for sublingual formulations. According to EP 1 710 245 B1 and EP 1 917 267 B1, the outcome of the micronisation process used therein, and which is necessary to reduce the particle size of the asenapine maleate crystals, appeared to be unpredictable when crystals of the monoclinic form of asenapine maleate were subjected to micronisation. Crystals of the orthorhombic form were found to be present in addition to the known monoclinic form of the starting material. The present inventors have also observed that micronisation of the monoclinic crystalline form of asenapine maleate, prepared as disclosed in U.S. Pat. No. 4,145,434, resulted in mixtures of both crystalline forms (i.e. monoclinic and orthorhombic forms of asenapine maleate), which eventually evolved to the orthorhombic crystalline form. This phenomenon does not seem to occur when the orthorhombic form of asenapine maleate is micronised, as described in EP 1 710 245 B1 and EP 1 917 267. However, use of the orthorhombic form in industry is unfeasible since its preparation process comprises very long crystallization steps (between 42-72 hours), as described in EP 1 710 245 B1 and EP 1917 267 B1. As a result, the preparation of micronised orthorhombic crystalline form of asenapine maleate is an undesirable process for industrial scale applications. More favourably, the preparation of the monoclinic form of asenapine maleate involves a crystallization process which only takes about 3 hours.
In accordance with regulatory requirements of the U.S. and other countries, e.g. the FDA's Good Manufacturing Practice (“GMP”) requirements, when preparing pharmaceutical compositions containing active ingredients for administration to mammals, there is a need to produce crystalline forms, or polymorphs, which are as pure and as stable as possible. Differences in the chemical and physical properties of polymorphic forms of active ingredients, such as melting point, chemical reactivity, handling properties and apparent solubility can have a direct effect on the ability to process and/or manufacture an active ingredient and its pharmaceutical compositions, as well as on its stability, dissolution rate and the bioavailability of commercial compositions. As a result, a process that provides unstable polymorphic forms is not desirable.
Therefore, it is highly desirable to develop a process which allows the reduction in size of the monoclinic form of asenapine maleate, such that it is suitable for the preparation of sublingual pharmaceutical compositions, yet following which the polymorphic stability of the asenapine maleate is maintained over time.